In:
Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 14, No. 20 ( 2008-10-15), p. 6405-6413
Abstract:
Purpose: The treatment of metastatic colorectal carcinoma represents a major clinical challenge. We investigated the hypothesis that the desmoplastic reaction within the liver elicited by metastatic adenocarcinoma, characterized by collagen I deposition and altered collagen IV distribution, promotes the growth and survival of hepatic colorectal carcinoma metastases. Experimental Design: Partial hepatectomy specimens for metastatic colorectal adenocarcinoma were examined immunohistochemically for differential integrin expression. Human colorectal adenocarcinoma cell lines HT-29, KM12SM, and KM12c were grown on wild-type collagen I or IV, or cleavage-resistant r/r collagen I, and assessed for their growth, survival, and resistance to 5-fluorouracil. The effect of αvβ3 and αvβ5 integrin blockade by neutralizing antibodies was examined. Results: Collagen I, in contrast to collagen IV, significantly enhanced the growth, survival, and chemoresistance of colorectal carcinoma cells. Blockade of the αvβ3 and αvβ5 integrins significantly reduced colorectal carcinoma cell proliferation on collagen, especially in the cell line with the most metastatic potential. These in vitro findings correlated with the pattern of integrin expression identified within resected hepatic colorectal carcinoma metastases. Using matrix metalloproteinase-resistant r/r collagen I as a dominant negative ligand for αv integrins, we showed a key role for this integrin-ligand interaction in mediating the survival and proliferation of colorectal carcinoma cells. Conclusions: Desmoplasia has an important role in the development of hepatic colorectal carcinoma metastasis. The interaction between integrin and collagen I is identified as a potential therapeutic target.
Type of Medium:
Online Resource
ISSN:
1078-0432
,
1557-3265
DOI:
10.1158/1078-0432.CCR-08-0816
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2008
detail.hit.zdb_id:
1225457-5
detail.hit.zdb_id:
2036787-9
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